Ketorolac tromethamine compositions for treating or preventing ocular pain

ABSTRACT

The present invention provides an aqueous ophthalmic solution comprising an effective amount of ketorolac which comprises carboxymethyl cellulose in an aqueous solution which provides increased visual acuity in users and wherein said concentration of carboxymethyl cellulose is selected to provide an increased absorption of ketorolac in the eye of a patient which is at least 130% greater than the absorption of a comparative aqueous ketorolac ophthalmic solution having the same concentration of ketorolac.

RELATED APPLICATION

This application claims the benefit of U.S. patent application Ser. No.12/396,131 filed on Mar. 2, 2009 pursuant to 35 USC 120 whichapplication claims the benefit of and priority to U.S. provisionalapplication Ser. Nos. 61/067,925 filed Mar. 3, 2008, 61/096,096 filedSep. 11, 2008, and 61/111,919 filed Nov. 6, 2008, and to AustralianPatent Application No. 2009202969 filed on Jul. 23, 2009 pursuant to 35USC 119, all of which prior applications are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions. Moreparticularly, this invention relates to topical ophthalmic solutionscomprising 5-benzyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid,otherwise known as ketorolac, and the use of ketorolac for treating orpreventing ocular pain.

DESCRIPTION OF THE RELATED ART

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are used tocontrol pain and postoperative inflammation. All drugs are associatedwith some adverse effects. With the use of NSAIDS in topical ophthalmictreatment of patients, surface toxicity has been a concern, andincidents of keratitis, corneal subepithelial infiltrates, ulceration,and corneal melts have been reported (Guidera et al, Opthalmology, 2001,108 (5), pp. 936-944; Solomon et al, J Cataract Refract Surg, 2001, 27(8), pp. 1232-1237; Teal et al, J Cataract Refract Surg, 1995, 21(5),pp. 516-518). Further, patients often report burning or stinging oninstillation (Jaanus et al, Antiinflammatory Drugs. Clinical OcularPharmacology, Bartlet, J. D. and Jaanus, S. D., Ed., Boston: Heineman,2001, pp. 265-298). The burning or stinging could be related to theconcentration of the active component of the formulation.

Ketorolac tromethamine 0.5% (w/v) ophthalmic solution, available fromAllergan, Inc., under the tradeneme ACULAR®, is a safe and effectiveNSAID with proven analgesic and anti-inflammatory activity. The mostcommon adverse event associated with the use of the 0.5% ketorolacformulation is ocular irritation, primarily burning and stinging uponinstillation. Ketorolac tromethamine 0.4% (w/v) ophthalmic solution,under the tradename ACULAR LS®, has shown improved bioavailability andless stinging on instillation than ACULAR®, but there remains a need foran improved ketorolac tromethamine formulation with greaterbioavailability and greater tolerability, minimized ocular surfacetoxicity, improved patient comfort, increased retention time of theactive ingredient and improved wound healing capabilities during use.

It is one object of this invention to provide a ketorolac formulationfor instillation in the eye to eliminate or reduce ocular irritation, toimprove tolerability, compliance, duration and effect of ketorolac, toallow for dosing from four times daily to twice daily, and to increasethe effectiveness of treatment by being free of benzalkonium chloride orother preservatives.

It is another object of the invention to improve bioavailability andincrease the ocular absorption of ketorolac yet provide an aqueoussolution having an optimized concentration of ketorolac.

It is another object of the invention to extend the effects of ketorolacand allow for a decrease in required daily dosage.

It is another object of the invention to provide reduction ofinflammation associated with cataract surgery and reduction of painassociated with cataract surgery in comparison to other ketorolacformulations.

It is another object of the invention to create a ketorolac formulationwith improved wound healing capabilities.

Other objects of this invention will become apparent from a reading ofthe present specification.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the ocular pharmacokinetics of the results in Example 7 ofthe increased and prolonged ketorolac exposure in the aqueous humor ofthe 0.45% w/v ketorolac solution in comparison to ACULAR LS®;

FIG. 2 shows the results of FIG. 1 in table form of Cmax, AUC andpercent relative bioavailability of the ocular pharmacokinetics inExample 7 of the aqueous humor relative bioavailability of 0.45% w/vketorolac solution in comparison to ACULAR LS®;

FIG. 3 shows the ocular pharmacokinetics of the results in Example 7 ofthe increased and prolonged ketorolac exposure in the iris-ciliary bodyof 0.45% w/v ketorolac solution in comparison to ACULAR LS®;

FIG. 4 shows the results of FIG. 3 in table form of Cmax, AUC andpercent relative bioavailability of the increased and prolonged exposurein the iris ciliary body of 0.45% w/v ketorolac solution in comparisonto ACULAR LS®;

FIG. 5 shows a multiple dose simulation of Example 7 of 0.45% ketorolacBID in comparison to ACULAR LS® QID in the iris ciliary body; and,

FIG. 6 shows safety and tolerability results in human clinical trials of0.45% w/v ketorolac solution vs. ACULAR LS.

SUMMARY OF THE INVENTION

The present invention provides an aqueous ophthalmic formulationcomprising an effective amount of ketorolac but having an optimizedconcentration of ketorolac in comparison other commercially availableketorolac products. The aqueous ophthalmic solution of the presentinvention comprises carboxymethyl cellulose, e.g. sodium carboxymethylcellulose, having a pH within the range of from about 6.8 to 7.4, whichis comfortable when topically applied to the eye of a patient, whereinthe concentration of carboxymethyl cellulose and, preferably, the pH, isselected to provide an increased absorption of ketorolac in the eye of apatient as compared to a comparative ketorolac solution that differsonly in not including the carboxymethyl cellulose. That is, theabsorption of ketorolac may be 130% or greater than the absorption of acomparative aqueous ketorolac ophthalmic solution having the same orhigher concentration of ketorolac.

More preferably, the aqueous ophthalmic solution of this invention has apH within the range of from 6.8 to 7.4, particularly 6.8.

More preferably, the aqueous ophthalmic solution of the presentinvention has a concentration of carboxymethyl cellulose of from about0.2 to about 2 percent, by weight, even more preferably from about 0.5to 1.5 percent, by weight, and most preferably about 0.5% w/v.

Even more preferably, the aqueous ophthalmic solution of the presentinvention comprises a mixture of medium viscosity and high viscositysodium carboxymethyl cellulose.

More preferably, the aqueous ophthalmic solution of the inventioncomprises an effective amount of ketorolac of from 0.25 to 0.50 percent,by weight, or about 0.45 percent, by weight.

More preferably, the aqueous ophthalmic solution of the invention has aviscosity of from 5 to 50 cps, preferably from 10 to 30 cps.

It has been surprisingly discovered that optimizing the concentration ofketorolac tromethamine reduces the occurrence of adverse events whilemaintaining clinical efficacy. Additionally, it has been discovered thatthe optimized concentration of ketorolac tromethamine in combinationwith carboxymethyl cellulose offers surprising and clear benefits interms of formulation in that no preservative, chelating agent, andsurfactant are required for formulation. Thus, finding a way to increasethe absorption of ketorolac benefits the patient who can use a solutionhaving an optimized concentration of ketorolac and obtain similarresults in terms of efficiency as compared to a ketorolac solutionhaving a higher concentration of ketorolac.

Thus, this invention relates to an aqueous topical ophthalmiccomposition comprising 0.25 to 0.50 percent by weight, more preferablyfrom 0.35% to 0.45% by weight and most preferably about 0.45% ketorolactromethamine by weight/volume. The present invention also contains from0.2 to 2 percent by weight, more preferably from 0.5 to 1.5 percent byweight and most preferably about 0.5% w/v percent of medium and highmolecular weight sodium carboxymethyl cellulose. Another aspect of thisinvention relates to a method of treating or preventing ocular pain in aperson comprising topically administering to said patient a sterilecomposition comprising from 0.25 to 0.50 percent, by weight, moreparticularly from 0.35% to 0.45% by weight, or about 0.45% w/v ketorolactromethamine in combination with from 0.2 to 2 percent, by weight,preferably from 0.5 to 1.5 percent by weight, and most preferably 0.5%percent by weight/volume, sodium carboxymethyl cellulose and mixturesthereof.

While not intending to limit the scope of this invention in any way, ofparticular interest in relationship to this invention is the use ofaqueous topical ophthalmic compositions of 0.45% (w/v) ketorolactromethamine for the treatment of ocular pain, especially for thetreatment of ocular pain in postoperative photorefractive keratectomy(PRK) surgery patients which improves healing. It is surprising that thelower concentration of ketorolac as compared to the Acular® product,discussed herein, would reduce the incidence of adverse events andenhance comfort while maintaining clinical efficacy. Two drops (0.1 mL)of 0.5% ketorolac tromethamine ophthalmic solution instilled into theeyes of patients 12 hours and 1 hour prior to cataract extractionachieved measurable levels in 8 of 9 patients' eyes (mean ketorolacconcentration 95 ng/mL aqueous humor, range 40 to 170 ng/mL). Ocularadministration of ketorolac tromethamine reduces prostaglandin E₂ (PGE₂)levels in aqueous humor. The mean concentration of PGE₂ was 80 pg/mL inthe aqueous humor of eyes receiving vehicle and 28 pg/mL in the eyesreceiving 0.5% ketorolac tromethamine ophthalmic solution.

Ocular administration of 0.45% w/v ketorolac tromethamine ophthalmicsolution increases relative bioavailability of ketorolac in the aqueoushumor of rabbits to greater than 200% and in the iris-ciliary body tonearly 300%, compared with 0.5% ketorolac tromethamine ophthalmicsolution. This enhanced ketorolac bioavailability allows for a reductionin dosing frequency from QID with 0.5% ketorolac tromethamine ophthalmicsolution to BID with 0.45% ketorolac solution. Preclinical data indicatesystemic ketorolac exposure levels achieved following ocularadministration of 0.45% ketorolac solution are comparable to levelsachieved with 0.5% ketorolac tromethamine ophthalmic solution.

DETAILED DESCRIPTION OF THE INVENTION

During the reformulation of Allergan's marketed Acular LS® product(0.40% w/v ketorolac), it was surprisingly found that a test formulationcontaining 0.45% ketorolac tromethamine and sodium carboxymethylcellulose (NaCMC) exhibited significantly better ocular absorption inrabbits than did the currently marketed product, i.e. Acular LS®.

Since the viscosities of the two test solutions were virtuallyidentical, the mechanism for achieving increased ocular penetrationcompared to the control formulation cannot be accounted for only by theviscosity of the test solutions. In fact, a comparison of two identicalcarboxymethyl cellulose containing solutions which differ only in havingviscosity of 11 and 22 cps shows similar absorption of ketorolac intothe aqueous humor. While not wishing to be bound by theory, it isbelieved that there is a functional relationship between the sodiumcarboxymethyl cellulose and either the ketorolac or some component ofthe ocular surface that facilitates absorption of ketorolac.

All of the aqueous topical ophthalmic solutions of this invention arecontemplated for use in treating or preventing ocular pain. Preferably,all of the solutions of this invention are contemplated for use whensaid ocular pain is a result of photorefractive keratectomy surgery(PRK).

One important aspect of this invention is that the solutions of thepresent invention have a concentration of ketorolac tromethamine whichis optimized to reduce side effects, while maintaining clinical efficacyin treating ocular pain. As such, the concentration of ketorolactromethamine in compositions related to this invention is preferablyfrom 0.35% to 0.45% w/v, most preferably the concentration of ketorolactromethamine in the aqueous topical ophthalmic solution of thisinvention is 0.45% ketorolac tromethamine, by weight.

Carboxymethyl cellulose (CMC) is a carboxymethyl derivative of celluloseformed by the reaction of cellulose with alkali and chloroacetic acid.As a result of said reaction, carboxymethyl groups are bound to some ofthe hydroxyl groups of the glucopyranose units that make up the backboneof cellulose. The degree of substitution of carboxymethyl varies fromabout 0.6 to 0.95 per glucopyranose unit. CMC is used in aqueoussolutions usually as the sodium salt to increase viscosity.

Carboxymethyl cellulose is available in various molecular weights. Lowmolecular weight carboxymethyl cellulose has a Mw of about 90,000daltons and a 2% solution thereof will have a viscosity of about 1.1 cPat 25° C. Medium weight carboxymethyl cellulose has a Mw of about250,000 daltons. High molecular weight carboxymethyl cellulose has a Mwof about 700,000 daltons and a 2% solution will have a viscosity ofabout 12 cP at 25° C.

For the purpose of the present invention, it is desirable to use amixture of medium and high molecular weight sodium carboxymethylcellulose. For example, from 25/75 to 75/25 carboxymethyl cellulose,preferably from 30/70 to 70/30 and most preferably about 35/65medium/high molecular weight sodium carboxymethyl cellulose or mostpreferably a ratio of 0.325/0.175.

The fact that the concentration of ketorolac tromethamine incompositions related to this invention achieves greater or equalabsorption of ketorolac into the aqueous humor of the eye and includescarboxymethyl cellulose, allows the solutions of the present inventionto be prepared with no preservative, surfactant and chelating agent.This is a significant advantage over prior art ketorolac formulations aspreservatives, surfactants and chelating agents can cause irritation tothe eye resulting in less patient compliance and less effectiveness ofprior art ketorolac formulations.

The term preservative has the meaning commonly understood in theophthalmic art. Preservatives are used to prevent bacterialcontamination in multiple-use ophthalmic preparations, and, while notintending to be limiting, examples include benzalkonium chloride,stabilized oxychloro complexes (otherwise known as Purite®),phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, andthimerosal. Preferably, the ketorolac solution of the present inventionis preservative free.

The term surfactant used in this invention has the meaning commonlyunderstood in the art. Surfactants are used to help solubilize thetherapeutically active agent or other insoluble components of thecomposition. Anionic, cationic, amphoteric, zwitterionic, and nonionicsurfactants may all be used in this invention. If a surfactant isincluded in the solutions of this invention, preferably, a nonionicsurfactant is used. While not intending to limit the scope of theinvention, some examples of useful nonionic surfactants arepolysorbates, poloxamers, alcohol ethoxylates, ethylene glycol-propyleneglycol block copolymers, fatty acid amides, and alkylphenol ethoxylates,and phospholipids. Most preferably, the surfactant is an octylphenolethoxylate with an average of 40 ethoxylate groups. This type ofsurfactant, also known as octoxynol-40 or Igepal CA-897®, can bepurchased under the Igepal CA-897® tradename from Rhone-Poulenc.Preferably, the ketorolac solution of the present invention issurfactant free.

The term chelating agent refers to a compound that is capable ofcomplexing a metal, as understood by those of ordinary skill in thechemical art. Chelating agents are used in ophthalmic compositions toenhance preservative effectiveness. While not intending to be limiting,some useful chelating agents for the purposes of this invention areedetate salts like edetate disodium, edetate calcium disodium, edetatesodium, edetate trisodium, and edetate dipotassium. Preferably, theketorolac solution of the present invention is chelator free.

In addition to surfactants, preservatives, and chelating agents,tonicity agents and other excipients are often used in ophthalmiccompositions. Tonicity agents are often used in ophthalmic compositionsto adjust the concentration of dissolved material to the desiredisotonic range. Tonicity agents are known to those skilled in theophthalmic art, and, while not intending to be limiting, some examplesinclude glycerin, mannitol, sorbitol, sodium chloride, and otherelectrolytes. Preferably, the tonicity agent is sodium chloride.

One preferred embodiment of this invention relates to an aqueous topicalophthalmic composition comprising 0.4% ketorolac tromethamine, from 0.2to 2.0%, by weight, sodium carboxymethyl cellulose.

The most preferred embodiment of this invention relates to an aqueoustopical ophthalmic composition consisting of 0.45% (w/v) of ketorolactromethamine, 0.5% w/v of carboxymethyl cellulose sodium, e.g. a mixtureof medium and high viscosity sodium carboxymethyl cellulose, sodiumchloride, sodium citrate dehydrate, sodium hydroxide, hydrochloric acidand purified water.

Example 1

Unless otherwise specified, all steps in this procedure were carried outat room temperature. The following procedure was followed in accordancewith the amounts listed in Table 1 below. Purified water was chargedinto the main batch vessel. Mixing was initiated to produce a vortexsufficient to disperse and/or dissolve all product ingredients withoutexcessive aeration or foam formation. The following components wereadded directly into the vortex in order, allowing each to dissolvebefore adding the next: sodium chloride, calcium chloride, dihydratemagnesium chloride, hexahydrate, boric acid, sodium borate, sodiumcarboxymethyl cellulose as a an percent aqueous solution comprisingincluding a mixture of 65% medium molecular weight and 35% highmolecular weight carboxymethyl cellulose. The solution was mixed for nolonger than 15 minutes. A specified amount of 1N sodium hydroxide, wasthen added. The pH was checked and, if needed, was adjusted to 7.3 with1N sodium hydroxide or 1N hydrochloric acid. Ketorolac tromethamine wasthen added based on “as is” assay and mixed until completely dissolvedbased on visual inspection. When dissolved, the solution pH was againchecked and if needed adjusted to pH 7.3-7.5 (final target pH is 7.4)with 1N sodium hydroxide or 1N hydrochloric acid. Purified water wasthen added to bring the bulk solution to final volume and allowed to mixfor at least 15 minutes to ensure uniformity. The solution was thensterile filtered for use.

TABLE 1 0.4% Ketorolac Tromethamine Ophthalmic Solution of the InventionKetorolac Tromethamine 0.4% CMC, Med Visc. 0.65% CMC Low Visc. 0.35%Potassium chloride 0.14% Calcium chloride, dihydrate 0.060% Magnesiumchloride, hexahydrate 0.060% Boric acid .060% Sodium borate .1225%

Example 2

Unless otherwise specified, all steps in this procedure were carried outat room temperature. The following procedure was followed in accordancewith the amounts listed in Table 2 below. Purified water at 90% of batchsize was charged into the main batch vessel. Mixing was initiated toproduce a vortex sufficient to disperse and/or dissolve all productingredients without excessive aeration or foam formation. The followingcomponents were added directly into the vortex in order, allowing eachto dissolve before adding the next: sodium chloride, edetate disodium,octoxynol-40 (as a 70% stock solution) and benzalkonium chloride (as a10% stock solution). The amount of benzalkonium chloride added took intoaccount the assay of the stock solution used. The solution was mixed forno longer than 15 minutes. A specified amount of 1N sodium hydroxide,1.85 mL per liter of final bulk product, was then added. The pH waschecked and if needed was adjusted to 10.7-11.0 with 1N sodium hydroxideor 1N hydrochloric acid. Ketorolac tromethamine was then added based on“as is” assay and mixed until completely dissolved based on visualinspection. When dissolved, the solution pH was again checked and ifneeded adjusted to pH 7.3-7.5 (final target pH is 7.4) with 1N sodiumhydroxide or 1N hydrochloric acid. Purified water was then added tobring the bulk solution to final volume and allowed to mix for at least15 minutes to ensure uniformity. The solution was then sterile filteredfor use.

TABLE 2 0.4% Ketorolac Tromethamine Ophthalmic Solution (Comparative)Ketorolac Tromethamine 0.4% Edetate Disodium 0.015% NaCl 0.79%Benzalkonium Chloride 0.006% Octoxynol-40 0.003% Ph 7.4

Example 3

This example was prepared according to the procedure of Example 1,except that hydroxypropyl cellulose was used in place of the sodiumcarboxymethyl cellulose in an amount sufficient to provide a viscosityequivalent to the viscosity of the composition of Example 1.

Example 4

The following composition was manufactured on a volume basis at ambienttemperates from two principal parts. Each part is manufacturedseparately and then combined under controlled sequences to form asterile bulk product: the first part (Part 1) involves the dissolutionof carboxymethyl cellulose sodium in water followed by bulk heatsterilization, and the second part (Part 2) involves dissolution ofketorolac tromethamine and salts in water sterile filtration throng a0.2 micron membrane into a sterile pressure vessel. The sterile bulksolution is then clarity filtered through a 20 micron polypropylenemembrane filter into the filling machine reservoir.

The sterile post-clarity filtered solution is then filled by a UDfilling machine via blow-fill-seal process into UD vials using virginLDPE resin without colorant. The filling is done in an ISO Class 5environment. The nominal fill is 0.4 mL into 0.9 mL capacity vials.

TABLE 3 0.45% w/v Ketorolac Tromethamine Ophthalmic SolutionConcentration Ingredient Function (% w/v) Ketorolac tromethamine Active0.45% Carboxymethy cellulose Thickening Agent 0.325% Sodium (Med.Viscosity) Carboxymethy cellulose Thickening Agent 0.175% Sodium (HighViscosity) NaCl Tonicity Agent 0.7% Sodium Citrate Buffer 0.2% DihydrateSodium Hydroxide (1N) pH adjustment Adjust to pH 6.8 Hydrochloric Acid(1N) pH adjustment Adjust to pH 6.8 Purified Water Vehicle Q.S.

Example 5

Comparison of Aqueous Humor Ketorolac Pharmacokinetics Following aSingle Ocular Instillation of 0.45% Ketorolac Tromethamine Formulationswith Varying pH to Acular LS® in New Zealand White Rabbits.

Study Objectives:

1) To compare aqueous humor ketorolac pharmacokinetics following asingle ocular instillation of 0.45% ketorolac tromethamine formulationswith varying pH and Acular LS® to New Zealand White rabbits;2) This Example was designed to determine whether decreasing the pH ofthe composition would increase the absorption of ketorolac into the eye;and,3) In addition, one arm of this trial was designed to test the effect ofdecreasing viscosity of the composition from 22 cps to 11 cps.

The specifics of this study are as follows:

Rabbit Aqueous Humor Ketorolac Concentrations following Administrationof Three 0.45% Ketorolac Tromethamine Formulations and Acular LS

TABLE 4 Treatment Groups 0.45% Ketorolac Tromethamine 22 cps pH = 7.40.45% Ketorolac Tromethamine 22 cps pH = 7.2 0.45% KetorolacTromethamine 22 cps pH = 7.0 0.45% Ketorolac Tromethamine 11 cps pH =7.0 0.45% Ketorolac Tromethamine 22 cps pH = 6.8 Acular LS pH = 7.4Dosing Route: Topical ocular Animal Gender: NZW Rabbits/Female DosingRegimen Single dose, bilateral Timepoints: 1, 2 and 4 hrs post-dose #Rabbits: 3 rabbits/timepoint + 1 rabbit blank Total = 39 rabbitsTissues/Matrices: Aqueous Humor Bioanalysis: LC-MS/MS Data analysis:AUC_(0-t), C_(max)

The results of the study are reported in Table 5, below.

TABLE 5 PK Parameters AUC₀₋₄ ± SE C_(max) ± SD Formulation (ng · h/ml)(ng/ml) Relative % F* 0.45% CMC 22 cps 627 ± 51 265 ± 71  135 pH 7.4 w.o“outlier” 0.45% CMC 22 cps 713 ± 96 322 ± 153 153 pH 7.4 0.45% CMC 22cps 620 ± 50 240 ± 84  133 pH 7.2 0.45% CMC 22 cps 658 ± 73 268 ± 125142 pH 7.0 0.45% CMC 22 cps  939 ± 163 389 ± 258 202 pH 6.8 0.45% CMC 11cps 649 ± 74 347 ± 218 139 pH 7.0 Acular LS ® 465 ± 65 211 ± 106 100

Summary of the Results

The sodium carboxymethyl cellulose-containing formulations performbetter than Acular LS® with a relative bioavailability ranging from 133%(0.45% Keto 22 cps pH 7.2) to 202% (0.45% Keto 22 cps pH 6.8). However,there is not a clear pH effect—because the 0.45% Keto 22 cps pH 7.4 hasa relative bioavailability of 153%, although one anomalous result maybedriving this observation. Nevertheless, the solution having a pH of 6.8shows the best bioavailability.

Example 6

A multicenter, randomized, double-masked, parallel-group study iscarried out using the 0.4% ketorolac tromethamine formulations ofExamples 2 and 3. The study subjects consisted of 157 patients(78-79/group) undergoing unilateral PRK surgery. The key inclusioncriteria for the study is that each subject a) is a candidate forunilateral photorefractive keratectomy surgery (PRK) within 7 days afterthe initial visit, b) have best-corrected ETDRS visual acuity of 20/100or better, and c) is capable of wearing a soft bandage contact lens. Keyexclusion criteria are a history of refractive ocular surgery andsensitivity to study medication or its vehicle, Tylenol #3®, orOcuflox®. The patient demographics are shown in Table 6. A total of 157patients are enrolled with an age range of 20-66 years. There are nosignificant demographic differences between treatment groups.

TABLE 6 Patient Demographics n % Gender Female 91 58 Male 66 42 Age,mean ± SD 39 ± 10 Race Caucasian 148 94 Black 5 3 Hispanic 2 1 Asian 1 1Other 1 1

Each subject receives the Ocuflox® 5 min prior to study medication. Thestudy subjects then receive ketorolac tromethamine 0.4% ophthalmicsolution of Example 2 or Example 3, 1 drop QID for up to 4 days. Thenall subjects are then instructed to take Tylenol #3® as needed forintolerable pain (escape medication). Patients use electronic diarieswith date and time stamp to record the ocular pain they experience asone of the following: no pain; mild; moderate; severe; and intolerable.

The pain intensity is less for the subjects who receive the solution ofExample 2 during the first 12 hours post-PRK compared to those whoreceive the solution of Example 3. In particular, during the first 12hours post-PRK, the group that receive the solution of Example 2 hadfewer patients with severe or intolerable pain compared with the receivethe solution of Example 3. In particular, the median pain intensityreported by the group which receive the solution of Example 2 was 1grade less than with the group which receive the solution of Example 3(moderate vs. severe on a 5-point scale of 0=no pain to 4=intolerablepain). Additionally, pain intensity is also less for the group whichreceive compared with the group which receive the solution of Example 3.

This clinical study shows that the solution of invention provides agreater degree of absorption of ketorolac as compared to the solutionwithout sodium carboxymethyl cellulose despite the fact that thesolutions have the same concentration of ketorolac and are at the sameviscosity.

In summary, the 0.4% ketorolac formulation is clinically effective intreating post PRK ocular pain. In patients treated with 0.4 ketorolactromethamine—the patients treated with the solution comprising sodiumcarboxymethyl cellulose experienced significantly greater and fasterpain relief, and used less escape medication compared to the patientstreated with the solution comprising hydroxypropylcellulose.

Example 7 Rabbit Ocular Pharmacokinetic Evaluation of KetorolacTromethamine 0.45% NZW Rabbits/Female

Dosing Regimen: Single ocular dose, bilateralTimepoints: 0.5, 1, 2, 4, 8, 10 and 24 hrs post-doseTissues/Matrices: Aqueous Humor and Iris-ciliary body

Bioanalysis: LC-MS/MS

Data Analysis: Pharmacokinetic analyses and simulation

Conclusion

As shown in FIGS. 1-5, Example 7 shows there is an:

1) Increase in relative bioavailability of ketorolac as compared toAcular LS®;2) Increased ketorolac concentrations are maintained longer post-dose;and3) Together these data support a reduction in dosing frequency from4×/day to 2×/day.

As shown in FIG. 6, Acular 0.45% is safe and well-tolerated among humanpatients when given 5 times over a half-day and compares very favorablyto ACULAR LS.

Visual Acuity in Operative Eye

This summary of clinical safety (SCS) is based on 2 completed phase 3studies of identical design and on one completed phase 1 study. All 3studies support the safe use of a new formulation of ketorolactromethamine ophthalmic solution 0.45% w/v (henceforth referred to asketorolac 0.45%), an unpreserved formulation of ketorolac tromethamineophthalmic solution containing a mixture of medium and high-molecularcarboxymethyl cellulose (CMC). The formulation was used in the phase 3studies, which investigated the safety of ketorolac 0.45% in cataractsurgery patients. The phase 1 study investigated the safety of ketorolac0.45% in healthy adult volunteers.

The current labeling for approved formulations of ketorolac tromethamineophthalmic solution such as ACULAR LS® (0.40% w/v ketorolac) lists from20% to 40% transient stinging and burning on instillation. The 0.45%formulation used in the phase 3 studies that form the basis of thisapplication was developed, among other reasons, to improve comfort whenadministered in the eye, primarily by the addition of medium and highmolecular weight carboxymethyl cellulose and the removal of octoxynoland benzalkonium chloride (BAK).

Studies evaluated efficacy and safety of ketorolac 0.45% compared withvehicle (same composition without the active) for the treatment ofanterior chamber inflammation, ocular pain, and inhibition of surgicallyinduced miosis following cataract extraction with posterior chamberintraocular lens (TOL) implantation. Both studies demonstrated thatketorolac 0.45% was safe and well tolerated. No new or unexpected safetyfindings were observed in either study. In addition, ketorolac 0.45% wasfound to be very well tolerated with a very low incidence of burning andstinging.

Another study assessed the safety and tolerability of ketorolactromethamine ophthalmic solutions 0.35% and 0.45% compared with ACULARLS® 0.4% in healthy adult subjects. ACULAR LS® 0.4% was chosen forcomparison as it was known to be a better tolerated formulation thanoriginal ACULAR® (0.50% w/v ketorolac) due to the lower concentration ofketorolac and removal of BAK and octoxynol. Compared with ACULAR LS®0.4%, ketorolac 0.45% had a consistently lower incidence of ocularsymptoms such as burning/stinging and ocular discomfort when dosed 5times in 1 day. No new or unexpected safety findings were observed forany of the ketorolac formulations.

The ketorolac 0.45% formulation of the present invention wascharacterized in ocular and systemic ketorolac rabbit pharmacokineticand toxicokinetic studies, in addition to 1-day ocular tolerability,1-month ocular toxicity, and 6-day ocular wound healing studies. Fromthe results of these preclinical studies, 0.45% ketorolac tromethamineadministered twice per day was anticipated to deliver ketorolac toocular tissues that are efficacious but at lower levels than thosepreviously demonstrated to be safe in long term toxicology studies.

The phase 3 studies were of identical design, multi-center, randomized,double-masked, parallel group comparison studies conducted to assess thesafety and efficacy of ketorolac 0.45% compared with vehicle. Studypatients underwent cataract extraction surgery with posterior chamberIOL implantation. Ketorolac 0.45% or vehicle was self-administered bypatients (1 drop twice daily in the operative eye beginning on the daybefore surgery and continuing on the day of surgery through the first 2weeks following surgery) and administered by medical personnel (3 dropsduring the 2 hr prior to surgery and 1 drop after surgery). The safetyparameters assessed were adverse events, vital signs, intraocularpressure, visual acuity, biomicroscopy, and opthalmoscopic examinations.The studies consisted of 7 scheduled visits: screening (week −4 to day−2); randomization (day −3 to day −1); cataract surgery day; andpostoperative days 1, 3, 7, and 14. Patients receiving ketorolac 0.45%had a lower incidence of ocular adverse events and of adverse eventsthat led to discontinuation than patients receiving vehicle.

A phase 1 study, a single-center, randomized, double-masked, paired-eye,active-controlled study in healthy adult subjects assessing the safetyand tolerability of ketorolac tromethamine ophthalmic solutions 0.35%and 0.45% compared with ACULAR LS® 0.4% (5 doses administered on 1 day).Five times in one day, administered by site personnel, subjects received1 drop of ketorolac 0.45% in study eye/ACULAR LS® in fellow eye or 1drop of ketorolac 0.35% in study eye/ACULAR LS® in fellow eye. Thesafety parameters assessed were ocular symptoms, ocular comfort, adverseevents, vital signs, intraocular pressure, visual acuity, biomicroscopy,macroscopic bulbar hyperemia, and opthalmoscopic exam. The studyconsisted of 2 scheduled visits: screening (day −14 to day −1) anddosing day/exit (day 1). Ketorolac 0.45% had a consistently lowerincidence of ocular symptoms and signs compared with ACULAR LS® 0.4%.

TABLE 7 Description of Clinical Efficacy and Safety Studies NumberDiagnosis of Study Start date Design Subjects Gender M/F and Centers Enddate Control Active/control, Study entered^(a)/ Median Age InclusionSafety Locations Enrollment type Route & Regimen Objective completedDuration (Range) Criteria Endpoints 26 15 Oct. Randomized, ketorolacEfficacy 248/201 16 days 107/141 Planned Adverse events, United 2007double- 0.45% and safety 70 (40- cataract vital signs, States 15 Apr.masked, ophthalmic 89) extraction intraocular 2008 parallel, BID withpressure, vehicle- vehicle BID posterior visual acuity, controlledchamber biomicroscopy, IOL fundus implant examinations 22 19 Oct.Randomized, ketorolac Efficacy 263/222 16 days 111/152 Planned Adverseevents, United 2007 double- 0.45% and safety 69 (28- cataract vitalsigns, States 31 Mar. masked, ophthalmic 94) extraction intraocular 2008parallel, BID with pressure, vehicle- vehicle BID posterior visualacuity, controlled chamber biomicroscopy, IOL fundus implantexaminations Abbreviations: IOL = intraocular lens ^(a)Intent to treat(ITT) population

TABLE 8 Description of Clinical Safety Study Number Diagnosis of StudyStart date Design Subjects Gender M/F and Centers End date ControlActive/control, Study entered/ Median Age Inclusion Safety LocationsEnrollment type Route & Regimen Objective completed Duration (Range)Criteria Endpoints 1 03 Jul. Randomized, Ketorolac 0.35%, Safety 39/39 1day 14/25 Healthy Adverse events, United 2007 double- 0.45%, 5 drops 24(19- adult ocular symptoms, States 03 Jul. masked, ophthalmic 63)volunteers subject comfort 2007 paired-eye, ACULAR LS ® questionnaires,active- 0.4%, 5 drops vital signs, control intraocular pressure, visualacuity, macroscopic bulbar hyperemia, and biomicroscopy

In a two phase 3 studies pooled, more than ⅔ of patients in bothtreatment groups experienced at least 1 line of improvement in visualacuity from baseline to final evaluation. Two patients in each treatmentgroup had a decrease in visual acuity of >3 lines (0.6% [2/320] ofketorolac 0.45% patients, 1.3% [2/158] of vehicle patients).

The proportion of ketorolac 0.45%-treated patients who experienced atleast 3 lines of improvement was statistically significantly higher thanthe proportion of vehicle-treated patients (58.1% [186/320] of ketorolac0.45% patients, 41.1% [65/158] of vehicle patients, p<0.001).Statistical significance for the same comparison was observed in study−006 (p=0.002) but borderline significant in study −005 (p=0.054).

TABLE 9 Visual Acuity in Operative Eye: Final Evaluation Compared withBaseline (Safety Population) Study Study Pooled Ketorolac KetorolacKetorolac 0.45% Vehicle 0.45% Vehicle 0.45% Vehicle Change (lines)^(a)(N = 157) (N = 81) (N = 173) (N = 82) (N = 330) (N = 163) N 153 78 16780 320 158 ≧+3 91 (59.5) 36 (46.2) 95 (56.9) 29 (36.3) 186 (58.1) 65(41.1) <+3 62 (40.5) 42 (53.8) 72 (43.1) 51 (63.8) 134 (41.9) 93 (58.9)≧+2 to <+3 17 (11.1) 12 (15.4) 21 (12.6) 7 (8.8) 38 (11.9) 19 (12.0) ≧+1to <+2 28 (18.3) 12 (15.4) 31 (18.6) 19 (23.8) 59 (18.4) 31 (19.6) ≧0 to<+1 12 (7.8) 7 (9.0) 10 (6.0) 13 (16.3) 22 (6.9) 20 (12.7) ≧−1 to <0 4(2.6) 4 (5.1) 5 (3.0) 6 (7.5) 9 (2.8) 10 (6.3) ≧−2 to <−1 1 (0.7) 5(6.4) 3 (1.8) 6 (7.5) 4 (1.3) 11 (7.0) >−3 to <−2 0 (0.0) 0 (0.0) 0(0.0) 0 (0.0) 0 (0.0) 0 (0.0) ≦−3 0 (0.0) 2 (2.6) 2 (1.2) 0 (0.0) 2(0.6) 2 (1.3) ^(a)positive change represents improvement

In the phase 1 study, most subjects had no change in visual acuityduring treatment. Decreases in visual acuity during treatment withrespect to baseline were observed for 1 (5.0%) ketorolac 0.45%-treatedeye, 1 (5.3%) ketorolac 0.35%-treated eye, and 3 (7.7%) ACULARLS®-treated eyes.

Conclusions:

1) The impact of treatment on visual acuity favors ketorolac overvehicle;2) More than ⅔ of patients in both treatment groups experienced at least1 line of improvement in visual acuity from baseline to finalevaluation;3) Twice the percentage of patients in the vehicle group experienced adecrease in visual acuity of >3 lines; and,4) The ketorolac 0.45% w/v group experienced over 40% greater incidenceof patients experiencing at least 3 lines of improvement—a statisticallysignificant difference.

The present invention is not to be limited in scope by the exemplifiedembodiments, which are only intended as illustrations of specificaspects of the invention. Various modifications of the invention, inaddition to those disclosed herein, will be apparent to those skilled inthe art by a careful reading of the specification, including the claims,as originally filed. It is intended that all such modifications willfall within the scope of the appended claims.

1. A topical aqueous ophthalmic solution comprising ketorolactromethamine, mixtures of carboxymethyl cellulose, containing nopreservative and having a pH within the range of approximately 6.8-7.4.2. The topical aqueous ophthalmic solution of claim 1 wherein saidsolution improves visual acuity in a subject's eye.
 3. The topicalaqueous ophthalmic solution of claim 1 wherein the ketorolactromethamine is present in a concentration of approximately 0.40-0.45percent by weight/volume of total solution.
 4. The topical aqueousophthalmic solution of claim 1 wherein the carboxymethyl cellulose is acombination of medium and high viscosity sodium carboxymethyl cellulose.5. The topical aqueous ophthalmic solution of claim 1 wherein theketorolac tromethamine is present in a concentration of 0.45 percent byweight/volume.
 6. The topical aqueous ophthalmic solution of claim 5having a pH between of 6.8.
 7. The topical aqueous ophthalmic solutionof claim 5 wherein the concentration of carboxymethyl cellulose is from0.2 to 2 percent by weight.
 8. The topical aqueous ophthalmic solutionof claim 7 wherein the concentration of carboxymethyl cellulose is 0.5%by weight/volume.
 9. The topical aqueous solution of claim 5 wherein thesolution is surfactant and chelator free.
 10. The topical aqueoussolution of claim 8 for use in treatment of ocular pain associated withpostoperative photorefractive keratectomy.
 11. The topical aqueoussolution of claim 5 wherein the ophthalmic solution improves the visualacuity in a patient of at least one line of improvement.
 12. The topicalaqueous solution of claim 5 further comprising a mixture of medium andhigh viscosity sodium carboxymethyl cellulose, sodium chloride, sodiumcitrate dehydrate, sodium hydroxide, hydrochloric acid and purifiedwater and wherein the solution improves the visual acuity of a user. 13.The topical aqueous solution of claim 5 wherein the combination ofcarboxymethyl cellulose and ketorolac increases the absorption in theeye of a patient more than a solution of ketorolac alone.
 14. Thetopical aqueous solution of claim 1 wherein the ketorolac tromethamineis present as a racemic mixture of R-(+) and S-(−)-ketorolactromethamine.
 15. The topical aqueous solution of claim 5 wherein theviscosity is from 10 to 30 cps.
 16. The topical aqueous solution ofclaim 6 wherein the mixture of carboxymethyl cellulose is present in theamount of 0.5% percent by weight.
 17. The topical aqueous solution ofclaim 5 wherein the solution may be administered before or after eyesurgery to prevent ocular pain.
 18. The topical aqueous solution ofclaim 5 wherein the solution increases healing time of the eye after eyesurgery in comparison to ketorolac solutions containing a preservative.19. The topical aqueous solution of claim 4 wherein the topical aqueoussolution is instilled twice daily to achieve proper efficacy.
 20. Thetopical aqueous solution of claim 5 wherein the ophthalmic improvesvisual acuity in a user of at least three lines of improvement.